Breast cancer is the most commonly diagnosed malignancy among women today with nearly 200,000/1.7 million new cases diagnosed in the US/worldwide each year respectively. Since about 70% of breast tumors are positive for the estrogen receptor alpha (ERα)—a key oncogenic driver in this subset of tumors—several classes of therapies have been developed to antagonize ERα function, including 1) selective estrogen receptor downregulators (SERDs) of which fulvestrant is an example, 2) selective estrogen receptor modulators (SERMs) of which tamoxifen is an example and 3) aromatase inhibitors that reduce systemic levels of estrogen. These therapies have been largely effective in the clinic reducing occurrence and progression of ERα+ breast tumors. However there are on-target liabilities associated with these different classes of compounds. For example, tamoxifen has been shown to activate signaling activity in the endometrium leading to an increase in risk of endometrial cancers in the clinic (Fisher et al., (1994) J. Natl. Cancer Inst. April 6; 86 (7): 527-37; van Leeuwen et al., (1994) Lancet February 19; 343 (8895): 448-52). In contrast, since fulvestrant is a pure antagonist, it can lead to loss of bone density in post-menopausal women as ERα activity is critical for bone building. In addition to on-target side effects, clinical resistance is also beginning to emerge to these classes of ERα antagonists highlighting the need to develop next-generation compounds.
Several mechanisms of resistance have been identified using in vitro and in vivo models of resistance to various endocrine therapies. These include increased ERα/HER2 “crosstalk” (Shou et al., (2004) J. Natl. Cancer Inst. June 16; 96 (12): 926-35), aberrant expression of ERα coactivators/corepressors (Osborne et al., (2003) J. Natl. Cancer Inst. March 5; 95(5): 353-61) or loss of ERα altogether to allow ER-independent growth (Osborne C K, Schiff R (2011) Annu. Rev. Med. 62: 233-47).
In the hopes of identifying clinically relevant mechanisms of resistance, great effort has also recently gone into deeply characterizing the genetics of endocrine-therapy resistant metastases isolated from patients. Several independent labs have recently published the multitude of genetic lesions observed in the resistant vs the primary tumors (Li et al., (2013) Cell Rep. September 26; 4(6): 1116-30; Robinson et al., (2013) Nat. Genet. December; 45 (12): 1446-51; Toy et al., (2013) Nat. Genet. 2013 December; 45(12):1439-45). Among these are the highly recurrent mutations in the ligand-binding domain of ESR1 (gene which encodes ERα protein) found to be significantly enriched in about 20% of resistant tumors relative to endocrine therapy naive tumors (Jeselsohn et al., (2014) Clin. Cancer Res. April 1; 20 (7): 1757-67; Toy et al., (2013) Nat. Genet. 2013 December; 45 (12): 1439-45; Robinson et al., (2013) Nat. Genet. December; 45 (12): 1446-51; Merenbakh-Lamin et al., (2013) Cancer Res. December 1; 73 (23): 6856-64; Yu et al., (2014) Science July 11; 345 (6193): 216-20; Segal and Dowsett (2014), Clin. Cancer Res. April 1; 20 (7): 1724-6), suggesting the potential for these mutations to functionally drive clinical resistance. In contrast to the enrichment in ESR1 mutations observed in therapy-resistant tumors, mutations in other cancer-related genes failed to show such a robust enrichment strongly implying the importance of ERα mutations in promoting resistance (Jeselsohn et al., (2014) Clin. Cancer Res. April 1; 20 (7): 1757-67).
ER+ breast cancer patients on average are treated with seven independent therapies including chemotherapies and various anti-estrogen therapies such as tamoxifen, fulvestrant and aromatase inhibitors. Recent genomic profiling has revealed that the ERα pathway remains a critical driver of tumor growth in the resistant setting as activating mutations in ERα have emerged. Thus, it is critical that more potent ER-directed therapies be developed that can overcome resistance in the clinical setting. Hence, there is a need for novel compounds that can potently suppress the growth of both wild-type (WT) and ERα-mutant positive tumors.